Iron-Driven Ferroptosis in Diabetic Kidney Disease: From Molecular Mechanisms to Targeted Therapeutic Translation

Abstract

Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease worldwide, and current standard treatments cannot fully halt its progressive decline in renal function. Dysregulated iron metabolism and its downstream induction of ferroptosis — an iron-dependent, lipid peroxidation-driven form of regulated cell death — have now been recognized as a key pathogenic driver of renal injury in DKD. This narrative review systematically synthesizes up-to-date evidence on how aberrant iron uptake, storage and export in renal cells trigger ferroptosis, disrupt antioxidant defenses, and promote renal tubular damage, glomerular sclerosis and interstitial fibrosis. We clearly distinguish mechanistic findings from preclinical in vitro and in vivo studies from clinically validated observations, including emerging ferroptosis-related biomarkers detected in DKD patient cohorts. We further evaluate iron chelation, lipid peroxidation inhibition, and targeted antioxidant reinforcement as promising therapeutic strategies, while explicitly highlighting critical current limitations: the lack of fully validated, kidney-specific ferroptosis biomarkers, insufficient large-scale clinical trial evidence, poor targeted delivery to renal parenchyma, and unresolved safety risks of long-term iron modulation. In conclusion, targeting iron-driven ferroptosis represents a highly promising translational direction for DKD intervention, but rigorous validation of ferroptosis-related biomarkers, optimization of kidney-targeted delivery systems, and well-designed clinical trials are still required before these strategies can be reliably translated into routine clinical practice.

Graphical Abstract

Introduction

Diabetes mellitus has emerged as one of the most daunting global public health challenges in the 21^st century. According to the latest data from the International Diabetes Federation (IDF), approximately 536.6 million people aged 20–79 worldwide are living with diabetes, and this number is projected to increase to 783.2 million by 2045.¹ Diabetic kidney disease(DKD) is the most prevalent microvascular complication of diabetes, affecting approximately 30%–40% of diabetic individuals and becoming a major driver of end-stage renal disease (ESRD) globally, forcing many patients to rely on renal replacement therapy (dialysis or kidney transplantation) to survive.² From both clinical and pathological perspectives, the hallmark features of DKD include the development of proteinuria and a progressive decline in the glomerular filtration rate (GFR), along with renal structural changes such as thickening of the glomerular basement membrane (GBM), mesangial expansion, and tubular atrophy.³

Standard therapies—including tight control of blood glucose, blood pressure, and lipids, together with inhibition of the renin–angiotensin–aldosterone system—constitute the cornerstone of current DKD management. The introduction of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists has expanded the therapeutic armamentarium in the past decade.⁴ However, a residual risk of DKD progression persists despite these advances. A trial demonstrated that at a median follow-up of 2.62 years, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group. Specifically, canagliflozin reduced the relative risk of the primary composite renal endpoint by 30%; however, this also meant that a considerable proportion of patients still experienced the primary composite endpoint, defined as dialysis, transplantation, a sustained estimated glomerular filtration rate of <15 mL/min/1.73 m², a doubling of the serum creatinine level, or death from renal or cardiovascular causes.⁵ Multiple mechanisms—including persistent intrarenal inflammation, progressive fibrosis, tubulointerstitial injury, and metabolic memory—interact to sustain ongoing renal damage and nephron loss despite guideline-directed therapy. Consequently, current therapies slow but do not halt the progression of structural kidney damage. This therapeutic gap underscores the need to elucidate novel disease mechanisms underlying DKD progression and to identify new therapeutic targets.

Among the emerging mechanisms, dysregulated programmed cell death has been recognized as a driver of DKD progression. Classical programmed cell death pathways—including apoptosis, pyroptosis, RIPK-dependent necroptosis and Ferritinophagy—have been extensively investigated in DKD. These classical types exhibit biochemical, morphological, and regulatory profiles distinct from ferroptosis, and each faces explanatory limitations when applied to the full spectrum of renal cell demise observed in diabetic kidneys. Apoptosis is anti-inflammatory and caspase-dependent, preserving membrane integrity until clearance—which cannot account for the early tubular loss in DKD. Pyroptosis and necroptosis are pro-inflammatory but feature cell swelling and membrane rupture, driven respectively by NLRP3/caspase-1 and RIPK1/RIPK3 cascades. Ferritinophagy shares upstream iron dysregulation with ferroptosis but is characterized by morphologically distinct features, including organelle swelling and chromatin concentration, which distinguish it from the mitochondrial atrophy of ferroptosis.⁶ In contrast, ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death, defined biochemically by inhibition of the System Xc⁻ and GPX4, reduced glutathione, iron accumulation, and lipid peroxidation. Morphologically, it displays small mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondrial cristae, and outer mitochondrial membrane rupture—features that align with the ultrastructural alterations observed in diabetic kidneys. Its regulatory pathways and key genes are distinct from those of the classical pathways.⁷ These distinguishing features position ferroptosis as a non-canonical death modality that directly bridges the core metabolic derangements of diabetes to renal cell injury.

In recent years, accumulating evidence has demonstrated that ferroptosis is closely linked to the initiation and progression of DKD. Sustained hyperglycemia and metabolic imbalance disrupt iron homeostasis in kidney cells. Multiple studies have documented iron accumulation in kidney tissue from DKD patient biopsies, as well as in experimental models including streptozotocin-induced diabetic mice, db/db mice, and Beagle dogs with DKD, with iron deposition most pronounced in renal tubular epithelial cells.^8–11 Perturbed iron handling, including increased transferrin receptor 1-mediated uptake with impaired storage/export, expands the labile iron pool, promotes reactive oxygen species generation, and accelerates membrane lipid peroxidation.^12,13 In parallel, antioxidant defenses—especially the cystine/glutamate antiporter system Xc⁻–glutathione–glutathione peroxidase 4 axis—are often compromised, rendering ferroptosis more readily inducible under diabetic stress.^6,14 Ferroptosis induces the death of key renal cells through lipid peroxidation, triggering oxidative stress and sterile inflammation, which in turn drive fibrotic remodeling.^15,16 Despite these advances, several critical knowledge gaps remain. The upstream regulatory hierarchy governing ferroptosis activation in distinct renal cell types remains incompletely defined. The molecular basis for cell type-specific vulnerability of podocytes, tubular epithelial cells, and endothelial cells has not been systematically characterized. The clinical translation of ferroptosis-targeting strategies, including the identification of reliable biomarkers and the evaluation of therapeutic efficacy, remains largely unexplored.

Accordingly, this review has three main objectives. First, we systematically summarize the mechanisms by which iron dysregulation and ferroptosis contribute to the pathogenesis of DKD, with a focus on iron metabolism, lipid peroxidation, and antioxidant defense. Second, we evaluate the cell type-specific roles of ferroptosis in different renal compartments. Most importantly, we assess the therapeutic potential of ferroptosis-targeted interventions by collating evidence from human, animal, and cellular studies separately, which lays a foundation for the development of novel therapeutic agents and provides additional opportunities for early intervention and treatment.

Methodology

This study was designed as a narrative review aimed at providing a comprehensive overview of recent advances and ongoing challenges in the role of iron-mediated ferroptosis in diabetic kidney disease (DKD), with a particular focus on therapeutic implications. Unlike systematic reviews, narrative reviews permit a broader, more flexible synthesis of the literature to identify emerging mechanistic insights and translational directions.

A literature search was performed in PubMed, Scopus, and Web of Science for articles published between January 2020 and March 2026. The core search terms included combinations of “ferroptosis”, “iron metabolism”, “diabetic kidney disease”, “diabetic nephropathy”, “renal fibrosis”, “lipid peroxidation”, “oxidative stress”, “inflammation”, and “therapeutic strategy”, linked with Boolean operators (AND/OR).

Given the rapid expansion of research on iron-dependent cell death pathways and their application to renal pathology in recent years, this review prioritized literature published between January 2020 and March 2026 to capture the most current mechanistic findings and conceptual developments in DKD-related ferroptosis. However, to avoid temporal bias and ensure a solid theoretical foundation, landmark studies with milestone significance published prior to 2020 were also deliberately included. The criteria for identifying these earlier studies were: (1) highly cited foundational research defining core iron metabolism and ferroptosis concepts; (2) studies forming the basis of current understanding of renal iron dysregulation in diabetes; or (3) publications representing the first demonstration of a key pathogenic or therapeutic mechanism. Data were synthesized narratively and organized into thematic sections covering pathogenesis, biomarkers, and therapeutic strategies.

Mechanisms of Ferroptosis

Ferroptosis arises from the convergence of iron overload, unchecked lipid peroxidation, and failure of antioxidant defense systems. At the molecular level, dysregulated iron metabolism expands the labile iron pool and drives redox reactions, polyunsaturated phospholipids provide the substrate for membrane-damaging peroxidation, and collapse of the system Xc⁻–GSH–GPX4 axis and parallel protective pathways permits toxic lipid peroxides to accumulate. These interconnected events define the core machinery of ferroptosis and form the mechanistic basis for its contribution to disease.

Iron Metabolism Dysregulation

Iron homeostasis is maintained through the precise regulation of iron uptake, reduction, storage, mobilization, and efflux. Disruption of this homeostasis is a central upstream event that triggers ferroptosis (Figure 1).

Figure 1.

Iron metabolism dysregulation and ferroptosis-related renal injury. Cellular iron homeostasis is sustained by coordinated iron uptake, reduction, storage, mobilization, and efflux. Transferrin-bound Fe³⁺ is taken up through TFR1-mediated endocytosis and reduced by STEAP3, whereas non-transferrin-bound iron is imported via DMT1, ZIP, and calcium channels. Cytosolic Fe²⁺ contributes to the labile iron pool and can be stored in ferritin, released by NCOA4-mediated ferritinophagy, or exported by ferroportin. Disturbance of these processes leads to iron overload, enhances the Fenton reaction and ROS production, and causes oxidative injury to lipids, proteins, and DNA, thereby promoting ferroptosis and contributing to renal cell damage. The figures created by BioRender.

Fe³⁺ is primarily taken up by cells in the form of transferrin-bound iron (TBI) via transferrin receptor 1 (TFR1). The upregulated expression of this receptor increases iron influx and is associated with susceptibility to ferroptosis.^17,18 Afterward, Fe³⁺ is transported to the labile iron pool (LIP) via divalent metal-ion transporter-1 (DMT1) or ZRT/IRT-like proteins (ZIP). After being reduced to Fe2+ by the six-transmembrane epithelial antigen of prostate 3 (STEAP3), the iron ion is ultimately utilized by the organism. Iron ions not bound to transferrin enter cells as nontransferrin-bound iron (NTBI) through DMT1, ZRT/IRT-like proteins 8/14 (ZIP8/14), the L-type calcium channel (LTCC), and the T-type calcium channel (TTCC), among others.¹⁹

Within the LIP, Fe²⁺ is either stored in ferritin (composed of ferritin heavy chain 1, FTH1, and ferritin light chain, FTL) or utilized for the synthesis of heme and iron–sulfur clusters. Ferritinophagy, mediated by nuclear receptor coactivator 4 (NCOA4), results in the release of stored iron back into the LIP.^20,21 Iron export is exclusively mediated by ferroportin (FPN1/SLC40A1). Dysregulation of any of these steps—such as TFR1 expression upregulation, FPN1 expression downregulation, or NCOA4 activation—leads to iron overload, which in turn promotes the Fenton reaction and lipid peroxidation, ultimately triggering ferroptosis.^22,23 Therefore, iron uptake, reduction, storage, mobilization, and efflux are all intimately linked to ferroptosis, and precise regulation of these processes is essential for the prevention and treatment of ferroptosis-related diseases.

Lipid Peroxidation

Lipid peroxidation is the central execution step of ferroptosis and drives the oxidative damage to cellular membranes that ultimately leads to cell death.^14,24 This process involves the oxidative deterioration of polyunsaturated fatty acids (PUFAs) incorporated into membrane phospholipids.²⁵

The incorporation of PUFAs into membranes is a critical determinant of ferroptosis sensitivity. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies long-chain PUFAs with coenzyme A, enriching membranes with peroxidation-susceptible substrates.²⁶ ACSL4 inhibition suppresses lipid peroxidation and ameliorates ferroptosis-related injury.²⁷ ACSL4 is tightly regulated: Parkin-mediated ubiquitination inhibits its activity,²⁸ whereas lysosomal dysfunction promotes its accumulation and sensitizes cells to ferroptosis.²⁹

PUFA-phospholipids can change. This change is called peroxidation. It happens in two ways. One way uses enzymes. The other way does not use enzymes. There is an enzyme called 15-lipoxygenase. It is also known as ALOX15. This enzyme makes lipid hydroperoxides directly. Myocardial ischemia is a condition of the heart. In that condition, this process acts like a “burning point”.³⁰ 15-hydroperoxy-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE) is a lethal signaling lipid, whereas the enzyme iPLA₂β counteracts this signal by hydrolyzing and eliminating oxidized phospholipids.³¹ Nonenzymatic lipid peroxidation, driven by hydroxyl radicals generated from the Fenton reaction, plays a substantial role in this process.^25,32 The progressive accumulation of lipid peroxides results in the loss of membrane integrity, culminating in cell death.³³ Phospholipid peroxidation in immune cells not only impairs phagocytic function but also promotes resistance to ferroptosis-based therapies. Furthermore, lipid peroxidation serves as both the lethal execution mechanism of ferroptosis and a critical intervention node, with broad relevance to multiple disease contexts.³⁴

Antioxidant System Dysregulation

The system Xc⁻–GSH–GPX4 axis constitutes the core antioxidant pathway. The cystine/glutamate antiporter system Xc⁻ (SLC7A11/SLC3A2) mediates cystine uptake for glutathione (GSH) synthesis.¹⁴ SLC7A11 expression is regulated by transcription factors, including SOX2 and the androgen receptor.^35,36 GPX4 utilizes GSH to reduce lipid hydroperoxides to nontoxic lipid alcohols.³⁷ GPX4 synthesis is coupled to cystine availability via mTORC1 signaling.³⁸ Posttranslational modifications modulate GPX4 stability: S-palmitoylation by ZDHHC8 and arginine methylation by PRMT5 prevent its degradation.^39,40

Multiple pathways operate parallel to GPX4. FSP1 reduces coenzyme Q10 to ubiquinol, halting lipid peroxide propagation.⁴¹ DHODH provides mitochondrial defense by reducing ubiquinone.⁴² GSTP1 detoxifies lipid aldehydes through GSH conjugation,⁴³ whereas iPLA₂β hydrolyzes peroxidized phospholipids.⁴⁴

The mevalonate pathway supports both CoQ10 biosynthesis and selenoprotein translation.⁴⁵ IRE1α controls GSH synthesis by cleaving SLC7A11 mRNA.⁴⁶ Thus, the antioxidant network comprises interconnected systems whose dysregulation determines ferroptosis vulnerability.

Iron Metabolism Dysregulation in DKD

A growing body of clinical and experimental evidence tells us that iron metabolism gets dysregulated, and that’s closely tied to how DKD starts and gets worse. Look at the signs: altered iron levels in the body, iron deposits inside the kidney, and changes in the molecules that normally control iron—all of these point to one thing. Disturbed iron handling is really a consistent part of diabetic kidney injury. And here’s the key: excess iron isn’t just a sign of how severe the disease is. It actually does damage. It messes up renal cell function, makes oxidative stress worse, and makes the kidney more prone to ferroptotic cell death. So if we want to understand what drives DKD and find good therapeutic targets, we really need to figure out how iron builds up and what that does to specific types of kidney cells.

Renal Iron Accumulation

Renal iron accumulation is a hallmark pathological feature of diabetic kidney disease (DKD); accumulating evidence from studies at the human, animal, and cellular levels has provided direct or indirect evidence for renal iron deposition.

Epidemiological evidence from the National Health and Nutrition Examination Survey (NHANES) involving 1306 diabetic patients revealed that impaired iron metabolism is an independent risk factor for DKD. Specifically, decreased serum iron levels and increased serum ferritin levels were significantly associated with DKD risk, indicating a pattern of systemic iron dysregulation characterized by iron retention and redistribution.⁴⁷ A nationwide cross-sectional study further confirmed that iron and total iron-binding capacity (TIBC) are negatively correlated with DKD, albuminuria, and a low estimated glomerular filtration rate (eGFR), whereas ferritin exhibits a “J”-shaped nonlinear correlation with DKD, albuminuria, and a low eGFR.⁴⁸

Direct evidence of renal iron overload in human DKD has been obtained through advanced imaging techniques. A recent study utilizing routine MRI T2WI sequences to calculate the kidney-to-muscle signal intensity ratio (K/M-SIR) revealed a significantly lower K/M-SIR in DKD patients (2.66 ± 0.49) than in diabetic patients without DKD (2.94 ± 0.51) and healthy subjects (2.95 ± 0.55). Because lower signal intensity on T2WI indicates greater iron deposition, these findings provide direct noninvasive evidence of renal iron accumulation in DKD patients.⁴⁹ Moreover, K/M-SIR values correlated negatively with clinical parameters, including glycated hemoglobin levels, microalbuminuria levels, the albumin-to-creatinine ratio, and 24-hour urinary protein levels, establishing a link between renal iron load and disease severity.⁵⁰ Longitudinal experimental studies using blood oxygen level-dependent magnetic resonance imaging have similarly confirmed progressive renal iron overload in diabetes.

Renal iron accumulation was histologically confirmed by analyzing kidney tissue from diabetic patients. Examination of renal samples from patients with type 2 diabetes undergoing nephrectomy revealed increased iron deposition compared with that in nondiabetic controls, with significant correlations between renal iron content and urinary ferritin levels.⁴⁷ Immunofluorescence staining further demonstrated the colocalization of ferritin with senescence markers in kidney tissues from both diabetic mice and patients, indicating that iron accumulation is intimately linked to cellular aging processes in diabetic kidneys.⁵¹

Urinary ferritin is a useful biomarker: levels increase with diabetes duration, correlate with tubular injury markers, and reflect renal iron content. Urinary ferritin could serve as a noninvasive indicator of renal iron overload and early tubular damage, even in the absence of albuminuria.⁴⁷ A prospective study confirs that ferritin is an independent risk factor for massive proteinuria in type 2 diabetes, while high serum iron, transferrin, and GPX4 levels are independent protective factors.⁵²

Mendelian randomization studies have further established causal relationships between iron status and DKD. Genetic analysis revealed that ferritin levels have a causal effect on a decreased estimated glomerular filtration rate (OR = 0.937) and an increased risk of type 1 diabetes with renal complications (OR = 1.783). Conversely, TIBC was causally associated with a lower risk of both diabetic nephropathy (OR = 0.864) and type 1 diabetes with renal complications (OR = 0.743), reinforcing the protective role of adequate iron-binding capacity.⁵³ Machine learning algorithms have also identified multiple ferroptosis-related genes as potential diagnostic biomarkers for DKD.⁵⁴

Lower hemoglobin levels, potentially reflecting disturbed iron metabolism, are an independent risk factor for rapid eGFR decline in patients with type 2 diabetes and preserved renal function, suggesting that iron dysregulation may precede overt DKD.⁵⁵ Iron chelation with deferoxamine alleviates renal dysfunction in experimental models, further supporting the pathogenic role of iron accumulation.⁵⁶

The molecular mechanisms underlying renal iron accumulation involve dysregulation of iron transporters and regulatory proteins. In diabetic kidney tissue, TFR1 is downregulated while ferritin heavy chain (FTH) and light chain (FTL) are upregulated, indicating increased iron storage capacity.⁵⁷ The divalent metal transporter ZIP14 is significantly upregulated in diabetic nephropathy, contributing to increased ferrous iron levels in renal tubular cells.⁵⁸ Hepcidin and renin are upregulated while ferroportin (Fpn) is downregulated, suggesting impaired iron export as a mechanism of renal iron retention.⁵⁹ Proteomic analysis has confirmed iron metabolism dysregulation in DKD, with heme oxygenase 1 (HMOX1) emerging as a key protein positively correlated with harmful lipid metabolites.⁶⁰

Collectively, human evidence from epidemiological studies, imaging, histology, biomarkers, genetics, and molecular profiling converges to establish renal iron accumulation as a consistent and clinically significant feature of DKD, providing the foundation for iron-targeted therapeutic strategies. Notably, In diabetic patients, iron deficiency anemia is a common complication associated with diabetes-related inflammation and impaired iron mobilization. However, a paradoxical phenomenon exists: patients often exhibit systemic iron deficiency (approximately 60%), yet significant iron deposition occurs in the renal tubules. This paradox complicates iron supplementation, as renal iron overload may accelerate kidney damage. These findings suggest that systemic iron deficiency and renal iron overload coexist and that therapeutic strategies must address both aspects simultaneously.

Effect on Renal Cell Function

Beyond serving as a hallmark pathological feature of DKD, renal iron accumulation directly impairs the function of multiple intrinsic renal cell types through ferroptosis-related mechanisms (Figure 2). These effects are cell-type specific and involve distinct regulatory networks in podocytes, tubular epithelial cells, mesangial cells, and glomerular endothelial cells, collectively contributing to glomerular and tubulointerstitial injury as well as progressive renal dysfunction.

Figure 2.

Cell-specific effects of iron-induced ferroptosis in diabetic kidney disease. Iron-induced ferroptosis differentially affects multiple renal intrinsic cell types in diabetic kidney disease and contributes to proteinuria and fibrosis. In podocytes, PHGDH regulates ferroptosis through the YB1/SLC7A11 axis, while circRNA-mediated inhibition of miR-188-3p promotes GPX4 expression and reduces podocyte injury. In tubular epithelial cells, ceruloplasmin, DPEP1-mediated inhibition of the GSH/GPX4 pathway, and high glucose-induced ACSL4 activation promote ferroptosis, whereas VDR activation and SGLT2 inhibitors suppress ferroptosis and attenuate tubular injury. In mesangial cells, tRF3-IleAAT/ZNF281-associated ferroptosis signaling and ferrostatin-1 influence glomerulosclerosis. In glomerular endothelial cells, mesangial cell-derived SEMA3C activates NRP1/NRP2 signaling and promotes endothelial-to-mesenchymal transition, resulting in endothelial dysfunction. Through coordinated injury in these cell populations, iron-induced ferroptosis accelerates renal structural damage and functional decline in diabetic kidney disease. The figures created by BioRender.

Podocytes are really vulnerable to iron-induced ferroptosis. That’s because they’re postmitotic. When PHGDH is deficient, it makes podocyte injury worse—by promoting ferroptosis. But if you overexpress PHGDH, it actually protects podocytes. How? By stabilizing YB1 and boosting SLC7A11 expression.⁶¹ Then there’s hirsutine. It lessens podocyte ferroptosis in db/db mice, and it does this by turning down p53/GPX4 signaling, which cuts down iron and ROS levels.⁶² Swietenine works too—it activates the Akt/GSK-3β/Nrf2 pathway to put the brakes on ferroptosis in podocytes.⁶³ Tanshinone IIA also suppresses podocyte ferroptosis, but through a different route: the ELAVL1/ACSL4 axis.⁶⁴ And finally, a circular RNA—mmu_circRNA_0000309—regulates podocyte ferroptosis by sponging miR-188-3p, which ends up promoting GPX4 expression.⁶⁵

Renal tubular epithelial cells are the most extensively studied cell type involved in DKD-related ferroptosis. Single-cell transcriptomics revealed that proximal tubule subsets exhibit impaired repair activity, with ceruloplasmin regulating ferroptosis in PT(AQP4+) cells.² DPEP1 expression is upregulated in tubular cells and promotes ferroptosis via inhibition of the GSH/GPX4 axis; cilastatin reverses this effect.⁶⁶ High glucose levels promote the O-GlcNAcylation of ACSL4 through OGT, stabilizing ACSL4 and inducing ferroptosis.⁶⁷ EZH2 regulates tubular ferroptosis by epigenetically suppressing SLC7A11.⁶⁸ TRIM65 protects tubular cells by targeting IREB2 for degradation, but lactate-induced lactylation at K206 impairs this function.¹³

HIF-1α/HIF-2α equilibrium is critical for the regulation of tubular ferroptosis.⁶⁹ Vitamin D receptor activation inhibits tubular ferroptosis via Nrf2/HO-1 signaling.¹¹ Naringenin protects HK-2 cells through the SIRT1/FOXO3a pathway.⁷⁰ Berberine targets Nrf2 to inhibit AGE-induced ferroptosis.⁷¹ Sleeve gastrectomy attenuates tubular ferroptosis by inhibiting the TGF-β1/Smad3 pathway.⁷² Dapagliflozin and empagliflozin inhibit tubular ferroptosis and fibrosis through the Nrf2 and AMPK/GSK-3β/NRF2 pathways, respectively.^73,74

Mesangial cells contribute to glomerulosclerosis through excessive extracellular matrix (ECM) synthesis, and emerging evidence indicates that ferroptosis is critically involved in this process. In DKD models, high glucose directly triggers ferroptosis in mesangial cells, as demonstrated by increased lipid peroxidation, iron accumulation, and characteristic mitochondrial alterations. Mechanistically, several pathways have been implicated. First, the METTL3/YTHDF3 m6A axis promotes ferroptosis in human renal mesangial cells (HRMCs) by stabilizing transferrin receptor 1 (TfR1) mRNA, thereby enhancing iron uptake and sensitizing cells to ferroptotic death.⁷⁵ Second, the tRNA-derived fragment tRF3-IleAAT has been identified as a protective factor in mesangial cells. tRF3-IleAAT is downregulated in DKD, and its overexpression inhibits ferroptosis by targeting the 3’UTR of ZNF281, a zinc finger transcription factor that promotes ECM synthesis and ferroptosis. Knockdown of ZNF281 in high glucose-treated mesangial cells exerts an inhibitory effect on both ferroptosis and ECM synthesis, suggesting that the tRF3-IleAAT/ZNF281 axis represents a critical regulatory node linking ferroptosis to mesangial matrix expansion in DKD.⁷⁶

Glomerular endothelial cells (GECs) are essential for maintaining the glomerular filtration barrier, and their dysfunction is a key event in DKD pathogenesis. Recent evidence has established that ferroptosis is a major driver of GEC injury under diabetic conditions. Multiple mechanisms have been elucidated. First, high glucose activates the Lp-PLA2/LPC axis in GECs. Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyzes oxidized phospholipids to generate lysophosphatidylcholine (LPC), which disrupts eNOS/NO signaling and amplifies lipid peroxidation. The Lp-PLA2/LPC axis drives iron-dependent ACSL4/NOX1-mediated oxidative injury, leading to GPX4 depletion and ferroptotic cell death. Pharmacological inhibition of Lp-PLA2 with Darapladib suppresses ferroptosis and attenuates renal injury, whereas LPC administration exacerbates both.⁷⁷ Second, high glucose downregulates miR-223-3p expression in GECs, leading to derepression of its direct target inositol 1,4,5-trisphosphate receptor type 3 (ITPR3). This results in elevated intracellular calcium levels, which together with increased iron and lipid peroxidation promotes ferroptosis in GECs. Overexpression of miR-223-3p reverses high glucose-induced ferroptosis and ITPR3 dysregulation.⁷⁸ Additionally, glomerular endothelial cells are affected by mesangial cell-derived SEMA3C, which promotes endothelium‒mesenchymal transition via NRP1/NRP2.²

Take bone marrow mesenchymal stem cells, for example. They help reduce inflammation and fibrosis—by putting the brakes on ferroptosis. And they do that through the SLC3A2 and MAPK pathways.⁷⁹ Then you have natural compounds. Quite a few of them work, like leech granules. They’ve been shown to regulate iron metabolism in different types of kidney cells. So what do all these findings tell us? Basically, iron-induced ferroptosis doesn’t hit every cell the same way in DKD.⁸⁰ It affects podocytes, tubular cells, mesangial cells, and endothelial cells—each differently. That’s why we really need comprehensive treatment strategies.⁸¹

Role of Ferroptosis in DKD

In DKD, ferroptosis isn’t just some isolated way that cells die on purpose. It’s actually a dynamic process—one that’s tightly wrapped up with all sorts of kidney injury mechanisms. More and more evidence shows that ferroptosis pushes DKD forward by talking to oxidative stress, inflammatory signals, mitochondrial problems, and other harmful pathways. These connections do not just make kidney cells more likely to die from ferroptosis. They also create these self-feeding loops that make both glomerular and tubulointerstitial damage worse. So in the next sections, we’ll go over the main roles ferroptosis plays in DKD, with a special focus on how it interacts with oxidative stress and inflammation.

Interaction with Oxidative Stress

Oxidative Stress as a Driver of Ferroptosis

Under diabetic conditions, hyperglycemia-induced oxidative stress creates a permissive environment for ferroptosis. The accumulation of ROS, particularly hydroxyl radicals generated via the Fenton reaction, directly initiates lipid peroxidation by abstracting hydrogen atoms from polyunsaturated fatty acids in cellular membranes.⁸² Clinical evidence supports this connection, as the levels of ferroptosis-related biomarkers, including ACSL4, MDA, and ROS, are significantly elevated in DKD patients with high levels of proteinuria, while the GPX4 level is correspondingly reduced.⁵² These findings suggest that oxidative stress is not only a consequence of metabolic dysregulation in diabetes but also an upstream trigger that lowers the threshold for ferroptotic execution.

The Nrf2 antioxidant pathway serves as the primary defense against oxidative stress-induced ferroptosis. In diabetic kidney tissue, Nrf2 expression is suppressed, leading to a compromised antioxidant capacity and increased susceptibility to ferroptosis.⁸³ Endoplasmic reticulum stress triggers ferroptosis through the XBP1–Hrd1–Nrf2 pathway, in which XBP1 increases Hrd1 expression, leading to Nrf2 ubiquitination and degradation and thereby increasing cellular susceptibility to ferroptosis.⁸⁴ PDK4-mediated Nrf2 inactivation contributes to oxidative stress and diabetic kidney injury.⁸⁵ Salusin-β participates in a positive feedback loop with ferroptosis: high glucose upregulates expression of salusin-β, which inactivates Nrf2 signaling and contributes to ferroptosis, whereas ferroptosis activators further increase salusin-β expression.⁸⁶

Mitochondria as a Central Hub in the Crosstalk

Mitochondria do two things. They pump out a lot of ROS, and at the same time, they get hit hard by ferroptotic damage. In diabetic kidneys, ferroptosis makes tubular injury worse—through the HIF-1α/HO-1 pathway. When you inhibit ferroptosis, here’s what happens: HIF-1α and HO-1 go down, NADPH oxidase-driven ROS drops, and antioxidant enzymes start working better again. So really, mitochondrial dysfunction is like this central hub where redox imbalance meets ferroptotic cell injury in DKD.⁸⁷ Now, mitophagy—that’s the cell’s way of cleaning up broken mitochondria. And it does a lot of good. It limits ROS coming from mitochondria and stops ferroptosis from happening. If you can reactivate mitophagy, it shuts down STING signaling, which gets turned on by mitochondrial DNA leaking into the cytosol. That protects cells from ferroptotic death.⁸⁸ Restoring PINK1-mediated mitophagy? That lowers mitochondrial ROS and cuts down ferroptosis too.⁸⁹ And here’s another thing—targeting mitochondrial dysfunction helps fight ferroptosis by tweaking HMOX1, FTH1, and TFR1.⁹⁰

Nrf2/GPX4 Axis as a Core of the Defense System

Glutathione peroxidase 4—GPX4 for short—is basically the last line of defense against ferroptosis. It takes lipid hydroperoxides and turns them into harmless lipid alcohols, and it needs glutathione to do that. Now, in DKD, GPX4 levels and its activity both go down. That leaves cells wide open to ferroptotic death. Then you have the Klotho/p53 pathway. It controls SLC7A11 and GPX4 expression, but that’s not all—it also tweaks p53, TFR1, and ACSL4.⁵⁷ And here’s another piece: KAT2A-mediated H3K79 succinylation promotes ferroptosis by regulating SAT2 expression.⁹¹ So when you put all this together, the Nrf2/GPX4 axis really stands out as a key molecular barrier that keeps ferroptosis in check in diabetic kidneys.

Positive Feedback Loop Between Oxidative Stress and Ferroptosis

In DKD, oxidative stress and ferroptosis kind of fuel each other. It’s a cycle. Oxidative stress wears down your antioxidant defenses and pushes lipid peroxidation forward, which kicks off ferroptosis. Then ferroptosis messes up mitochondrial function and membrane integrity, pumping out even more ROS and making oxidative damage worse. So they just keep amplifying each other. That creates a self-perpetuating cycle, and that cycle speeds up kidney damage and loss of function. Notably, ferroptosis inhibition attenuates ROS generation, lowers MDA and iron accumulation, and upregulates antioxidant enzyme expression, demonstrating that interference with ferroptosis effectively breaks the vicious cycle of oxidative damage.⁸⁷ On the flip side, if your antioxidant capacity is weak, cells are just more likely to die from ferroptosis.⁹²

Other Interactive Mechanisms

Beyond the oxidative stress-ferroptosis circuit, additional signaling pathways modulate ferroptosis sensitivity in DKD. AMP-activated protein kinase (AMPK) serves as a central energy sensor linking metabolic stress to ferroptosis execution. High glucose inactivates AMPK in diabetic kidneys, promoting ferroptosis, whereas AMPK activation enhances resistance to ferroptosis and protects against kidney injury. Mechanistically, AMPK exerts its antiferroptotic effects through at least three interconnected pathways. First, AMPK phosphorylates acetyl-CoA carboxylase (ACC) to suppress fatty acid synthesis and promote fatty acid oxidation, thereby limiting the accumulation of lipid peroxidation substrates. Second, AMPK promotes PINK1/Parkin-dependent mitophagy to clear damaged mitochondria and reduce mitochondrial ROS production.⁹³ Third, AMPK activates the NRF2 antioxidant pathway, upregulating GPX4 and SLC7A11 expression to reinforce cellular defenses against lipid peroxidation.⁹⁴ Collectively, these mechanisms position AMPK as a critical node integrating metabolic regulation, antioxidant defense, and mitochondrial quality control in ferroptosis suppression.

Summary

Overall, oxidative stress and ferroptosis engage in tightly coupled bidirectional crosstalk in DKD. Mitochondrial dysfunction, suppression of the Nrf2/GPX4 defense axis, and dysregulation of multiple metabolic and stress-response pathways collectively integrate these processes. This conceptual framework supports therapeutic strategies that simultaneously target oxidative stress and ferroptosis to disrupt the self-amplifying cycle of renal injury.

Inflammation and Ferroptosis

In DKD, inflammation and ferroptosis form a bidirectional regulatory network, each amplifying the other. Diabetic nephropathy is fundamentally a chronic inflammatory disease, and inflammatory activation is tightly linked to ferroptosis initiation and progression. Hyperglycemia triggers iron overload, lipid peroxidation, oxidative stress, inflammation, and fibrosis—all mechanistically intertwined in DKD.

HMGB1 links inflammation and ferroptosis. In diabetic nephropathy, HMGB1 is elevated along with ACSL4, PTGS2, and NOX1, while GPX4 is reduced. High glucose drives HMGB1 from nucleus to cytoplasm, activating TLR4/NF-κB and upregulating IL-6 and TNF-α, while also suppressing Nrf2 and downstream HO-1 and NQO-1. HMGB1 thus controls ferroptosis through this dual regulation; HMGB1 inhibition reduces inflammation and normalizes ferroptosis-related genes.⁹⁵ IL-6 participates in immunoinflammation, metabolism, hemodynamics, and ferroptosis in DKD; elevated IL-6 correlates with disease severity and may serve as a biomarker for inflammation-dominant DKD.⁹⁶

Ferroptosis intersects with other programmed cell death pathways that drive inflammation. PANoptosis integrates pyroptotic, apoptotic, and necroptotic signals; ferroptosis interacts with these pathways, collectively contributing to kidney damage. ROS and mitochondrial damage link ferroptosis to NLRP3 inflammasome-mediated pyroptosis.⁹⁷ The crosstalk between ferroptosis and these regulated cell death pathways in DKD is illustrated in Figure 3.

Figure 3.

Crosstalk between ferroptosis and other regulated cell death pathways in diabetic kidney disease. Hyperglycemia and chronic inflammation drive iron overload and lipid peroxidation, triggering ferroptosis. Ferroptosis intersects with necroptosis via RIPK1/RIPK3/MLKL pore formation and with pyroptosis via caspase-8-mediated GSDMD cleavage. Autophagy/ferritinophagy serves as a core hub, promoting ferritin degradation and iron release, which amplifies ferroptotic signaling. Reactive oxygen species (ROS) production further activates inflammatory pathways, creating a self-amplifying loop that contributes to DKD-associated renal injury. Solid arrows indicate direct activation or progression. The figures created by BioRender.

Circular RNAs regulate the inflammation–ferroptosis interplay. Circ ASAP2 reduces inflammation and ferroptosis via SOX2/SLC7A11 by sponging miR-770-5p; its downregulation promotes inflammation, oxidative stress, and ferroptosis.⁹⁸ SLC7A11 and GPX4 serve as a critical node integrating inflammation and ferroptosis; SLC7A11/GPX4 activation mitigates both.⁹⁹

Systems pharmacology and multi-omics analyses indicate that targeting certain pathways simultaneously affects renal ferroptosis, renal inflammation, and podocyte insulin resistance, confirming these processes are mechanically linked and coregulated.¹⁰⁰ GPX4 pathway activation relieves iron overload and reduces ferroptosis while also reducing inflammation.¹⁰¹ Nrf2 activation suppresses oxidative stress, inflammation, and ferroptosis simultaneously, highlighting its central role in integrating the cellular response to diabetic injury.¹⁰²

The involvement of immune cells further underscores the link between inflammation and ferroptosis. Immune infiltration analysis has revealed that ferroptosis-related genes are closely associated with immune cell populations. Six hub genes—Ccl5, Il18, Cybb, Fcgr2b, Myd88, and Ccr2—were identified, of which Fcgr2b, Cybb, Ccr2, and Ccl5 were strongly linked to M2 macrophage and γδ T cell infiltration.¹⁰³ ALOX5 has been identified as an immune-related ferroptosis biomarker, correlating positively with M1 macrophages, γδ T cells, and monocytes.¹⁰⁴

In summary, inflammation and ferroptosis engage in bidirectional crosstalk in DKD. Inflammatory mediators modulate cellular sensitivity to ferroptosis, while ferroptotic cell death releases danger signals and oxidized lipids that further amplify inflammatory responses. Key molecular players—including HMGB1, IL-6, the SLC7A11/GPX4 axis, and Nrf2—coordinate this reciprocal regulation, providing a mechanistic rationale for developing therapeutic strategies that simultaneously target both inflammation and ferroptosis in DKD. The integration of ferroptosis pathways with the pathological progression of DKD is summarized in Figure 4, which provides a visual synthesis of the mechanisms discussed in this chapter and their contribution to DKD progression.

Figure 4.

Integration of ferroptosis pathways with diabetic kidney disease progression. The figure illustrates the stepwise relationship between ferroptotic pathways and the pathological progression of DKD. In early DKD, iron metabolism dysregulation—characterized by TFR1 upregulation, FPN1 downregulation, and NCOA4-mediated ferritinophagy—leads to Fe²⁺ accumulation and mitochondrial injury in tubular epithelial cells. In middle DKD, the lipid peroxidation pathway, driven by ACSL4 and LPCAT3, generates lipid ROS and damages podocytes and endothelial cells, manifesting as proteinuria. In late DKD, failure of the antioxidant defense (system Xc⁻/GSH/GPX4 axis) permits lethal lipid peroxide accumulation, triggering ferroptotic cell death, subsequent inflammation, and fibrotic remodeling. The bottom panels show the final clinical consequences: podocyte loss, tubular injury, proteinuria, progressive eGFR decline, and end-stage renal disease. Solid arrows indicate direct progression; dashed arrows indicate indirect or contributory relationships. The figures created by BioRender.

Core Clinical Phenotypes

The way DKD shows up in patients is pretty varied. That variety actually reflects what’s going on underneath—iron dysregulation and ferroptosis. So if we start recognizing clinical patterns that are linked to ferroptosis, that could help us in a few ways. Earlier diagnosis, better predictions of how the disease will progress, and maybe even sorting patients into groups that would benefit from targeted therapies.

Proteinuria and Glomerular Injury

Proteinuria serves as the cardinal clinical hallmark of DKD, directly reflecting glomerular injury with predominant involvement of podocytes. Podocytes exhibit heightened susceptibility to ferroptosis, attributable to their postmitotic nature and limited capacity for regeneration. Consequently, podocyte injury disrupts the glomerular filtration barrier, culminating in protein extravasation.

There’s solid clinical evidence linking ferroptosis-related biomarkers to how bad proteinuria gets. Take one prospective study—118 patients with type 2 diabetes. The ones with really high proteinuria also had much higher levels of ferroptosis markers like ACSL4, MDA, and ROS. Meanwhile, their GPX4 levels were significantly lower. And here’s what multivariate logistic regression showed: ferritin levels came out as independent risk factors for massive proteinuria. On the flip side, high levels of serum iron, transferrin, and GPX4 were independent protective factors.⁵²

The diagnostic value of ferroptosis-related biomarkers has been validated across multiple studies. A combination of GPX4, ACSL4, MDA, and ROS demonstrated good predictive value for DKD, yielding an area under the ROC curve of 0.804.⁵² Moreover, in patients with biopsy-proven DKD, renal tubulointerstitial GPX4 expression levels correlated significantly with proteinuria (r = −0.42), the urinary albumin-to-creatinine ratio (r = −0.40), and the percentage of sclerosed glomeruli (r = −0.42).¹⁰⁵

Circular RNAs are starting to look like promising biomarkers for proteinuric DKD. Take circ-0069561, for example. Its expression goes way up in the kidney tissue of both type 2 diabetic mice and DKD patients, and it’s mostly found in the glomeruli. When they ran an ROC curve analysis, circ-0069561 turned out to have excellent diagnostic value for high levels of proteinuria—AUC of 0.889. Plus, high expression of this circRNA was linked to a greater risk of primary endpoints. And in vitro experiments confirmed it: circ-0069561 makes glucose-induced podocyte damage and ferroptosis worse.¹⁰⁶

Glomerular endothelial cells play a role in proteinuria too, and ferroptosis is behind it. Here’s how: high glucose lowers miR-223-3p expression. That, in turn, raises calcium levels inside the cells via ITPR3, and then ferroptosis kicks in. The result is that the glomerular filtration barrier gets damaged.⁷⁸ Then there’s the Lp-PLA2/LPC axis. It drives endothelial ferroptosis in DKD. And as this axis becomes more active, you see a clear link with albuminuria, endothelial dysfunction, and actual ferroptotic cell death.⁷⁷

Nonproteinuric DKD and Rapid eGFR Decline

Proteinuria has always been seen as the classic sign of DKD. But here’s the thing—a growing number of patients show up with a different picture. They have nonproteinuric DKD. That means their eGFR drops quickly, yet there’s no major albuminuria. This kind of presentation is hard to diagnose. And it might be due to ferroptosis-related mechanisms that hit the tubulointerstitium harder than the glomerulus.

So here’s something interesting. Lower hemoglobin levels—which might point to messed-up iron metabolism—have been found to be an independent risk factor for rapid eGFR decline. And this is in type 2 diabetes patients whose kidney function is still preserved. There was this multicenter cohort study with 242 patients. All of them had a baseline eGFR of 60 or higher (that’s mL/min/1.73 m²) and normal albumin levels. They were followed for about 6.7 years on average. What did they find? Patients with lower baseline hemoglobin were significantly more likely to show rapid declines—meaning a drop of at least 3.3% per year. Also, baseline hemoglobin levels went up along with iron and ferritin levels.⁵⁵ That suggests impaired iron metabolism might actually be causing those lower hemoglobin levels in the rapid decliners. And here’s the kicker: these disturbances might even happen before DKD develops.

ACSL4, a key ferroptosis driver, predicts rapid kidney function decline in patients with DKD. In a retrospective cohort of 72 biopsy-proven DKD patients followed for a median of 23 months, tubular ACSL4 expression levels were significantly higher in DKD patients than in controls, positively correlated with proteinuria, and negatively correlated with albumin and hemoglobin levels at biopsy. ACSL4 was negatively correlated with the eGFR slope, and patients in the top tertile of baseline ACSL4 were at high risk for rapid kidney function decline. This study revealed that in DKD patients without significant proteinuria, high expression of ACSL4 in renal tubules can also independently predict the risk of rapid eGFR decline.¹⁰⁷

Aggravating Factors of Acute Kidney Injury in DKD: The “Second Hit” Role of Ferroptosis

Patients with DKD exhibit significantly increased susceptibility to acute kidney injury (AKI). Chronic diabetes acts as the first hit, resulting in renal tubular epithelial cells being in a stress-sensitized state; upon superimposed acute stress, such as ischemia–reperfusion (the second hit), these cells rapidly undergo ferroptosis, thereby inducing or exacerbating AKI. This framework helps explain the high incidence and severe clinical course of AKI in patients with DKD.

Several independent studies have verified the involvement of ferroptosis in DKD-related renal injury and elevated AKI susceptibility via distinct molecular pathways. Proximal tubular epithelial cells in DKD patients exhibit impaired autophagy, inactivated AMPK signaling, and high expression of ferroptosis markers; animal experiments further confirmed that defective autophagy and AMPK inactivation increase ferroptosis susceptibility in the renal tubules of diabetic mice, whereas activation of both pathways can alleviate renal injury and reduce AKI risk.⁹³

In addition, iron overload and aggravated oxidative stress in type 2 diabetic mice activate the HIF-1α/HO-1 pathway to mediate ferroptosis, worsening renal tubular damage and fibrosis; intervention with ferroptosis inhibitors effectively reverses these pathological changes, verifying the involvement of this pathway in ferroptosis-mediated DKD-related renal injury.⁸⁷

Moreover, the protective molecule RRM2 inhibits oxidative stress and ferroptosis in renal tubular epithelial cells via the PI3K/Akt pathway, exerting renoprotective effects; however, the impaired protective function of RRM2 under diabetic conditions further increases cellular susceptibility to injury and promotes the occurrence of DKD complicated with AKI.¹⁰⁸

Collectively, these findings support the concept that ferroptosis acts as a critical “second hit” mechanism in DKD-associated AKI, with multiple diabetes-induced abnormalities converging to increase tubular vulnerability to acute stress.

Cardiorenal Syndrome Risk

DKD rarely occurs in isolation; it is frequently accompanied by cardiovascular disease, together constituting cardiorenal syndrome. Ferroptosis has emerged as a common pathogenic mechanism linking renal and cardiac injury in diabetic patients.

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease reveals that iron imbalance is the common denominator in many subtypes of cardiovascular disease, including atherosclerosis, drug-induced heart failure, myocardial ischemia‒reperfusion injury, and diabetic cardiomyopathy.³³ These conditions share pathophysiological features with DKD, suggesting that ferroptosis-targeted therapies may provide dual organ protection.

Clinical evidence supports the association between ferroptosis markers and cardiorenal risk. In patients with type 2 diabetes, the combination of GPX4, ACSL4, MDA, and ROS exhibited a good predictive value for DKD,⁵² and these same markers are implicated in cardiovascular disease progression. The identification of common ferroptosis-related mechanisms suggests that therapeutic strategies targeting ferroptosis may simultaneously ameliorate both renal and cardiovascular complications in diabetic patients.

Biomarker Development and Future Clinical Applications

Several ferroptosis-related biomarkers have shown promise for DKD diagnosis and progression monitoring. Circulating GPX4, ACSL4, and MDA levels are significantly altered in DKD patients and correlate with proteinuria severity and eGFR decline. Urinary ferritin has emerged as a noninvasive indicator of renal iron overload and early tubular damage, even in the absence of albuminuria. However, several critical gaps impede clinical translation. First, assay standardization across laboratories is lacking, with varying cut-off values and detection methods reported across studies. Second, the predictive value of these biomarkers for treatment response has not been prospectively validated in independent cohorts. Third, whether these biomarkers can guide patient selection for ferroptosis-targeted therapy remains unexplored. Future studies should prioritize prospective cohort studies to establish standardized reference ranges and validate the utility of these biomarkers in predicting therapeutic outcomes. Additionally, the combination of multiple biomarkers—rather than single markers—may offer superior diagnostic and prognostic accuracy, as ferroptosis involves interconnected pathways of iron metabolism, lipid peroxidation, and antioxidant defense (Figure 5).

Figure 5.

Translational framework of ferroptosis in diabetic kidney disease: from mechanisms and biomarkers to targeted intervention. A clinically actionable anti-ferroptosis strategy in diabetic kidney disease (DKD) evolves through a stepwise translational pathway. Mechanistic drivers, including iron metabolism dysregulation, lipid peroxidation, and antioxidant system dysregulation, provide the biological basis for biomarker discovery. Candidate biomarkers include circulating GPX4, ACSL4, MDA, and ROS; urinary ferritin; and tissue GPX4 expression and circ-0069561. These biomarkers may guide tailored interventions, including iron regulation, reinforcement of antioxidant defenses, and anti-inflammatory combination therapy. Major translational barriers remain, including limited human validation, disease heterogeneity, and limited analytical techniques. Overcoming these hurdles is critical to realizing precision targeted ferroptosis therapy for individual DKD patients. The figures created by BioRender.

Therapeutic Targets

Relationship Between Ferroptosis Targeting and Existing DKD Therapies

Ferroptosis-targeted strategies should not be viewed as replacing current DKD therapies but rather as complementing them. RAAS inhibitors and SGLT2 inhibitors primarily address hemodynamic and metabolic drivers of DKD—lowering intraglomerular pressure, reducing albuminuria, and improving glycemic control. In contrast, ferroptosis inhibitors target a distinct pathogenic pathway: iron-dependent lipid peroxidation and regulated cell death. The residual renal risk observed in clinical trials even with optimal RAAS blockade and SGLT2 inhibitor therapy suggests that pathways like ferroptosis may remain active despite standard care. Therefore, combination approaches integrating ferroptosis inhibitors with existing therapies may provide additive renoprotection by simultaneously targeting multiple pathogenic mechanisms. However, potential interactions between these therapies require careful evaluation. For instance, SGLT2 inhibitors have been shown to exert antiferroptotic effects in animal models, suggesting that some current DKD therapies may already modulate ferroptosis pathways.⁷³ Understanding these mechanistic overlaps will be essential for designing rational combination strategies and avoiding redundant targeting.

The recognition of ferroptosis as a major pathogenic mechanism in DKD has substantially broadened the therapeutic landscape. Current evidence suggests that ferroptosis-targeted interventions in DKD mainly converge on three interconnected levels: regulation of iron metabolism, reinforcement of antioxidant defense systems, and modulation of inflammation–ferroptosis crosstalk. These mechanisms are highly integrated rather than independent. In practice, many candidate agents simultaneously affect iron handling, lipid peroxidation, redox homeostasis, and inflammatory signaling, suggesting that multitarget or combination strategies may ultimately be required for effective clinical translation. The currently reported interventions can be broadly categorized into strategies targeting iron metabolism, antioxidant defense systems, and inflammation–ferroptosis crosstalk (Tables 1–3).

Table 1.

Therapeutic Strategies Targeting Iron Metabolism and Ferroptosis Initiation in Diabetic Kidney Disease

Therapeutic Category	Representative Agents/Strategies	Evidence Source	Translational Stage	Primary Target	Main Mechanism	Histopathological Changes	Renal Function Indicators
Inhibition of iron uptake	Vitamin D57	Human: kidney tissue from prediabetic patients; Animal: DKD mouse models; Cell: high glucose-treated renal tubular epithelial cells	Clinical translation	TFR1	Downregulation of TFR1 reduces intracellular iron influx and ferroptosis susceptibility	Reduced tubular iron deposition, attenuated tubular atrophy, decreased mesangial matrix expansion	Reduced proteinuria, improved eGFR, decreased urinary albumin-to-creatinine ratio (UACR)
	Astragaloside IV60,90	Animal: STZ-induced and db/db diabetic mice; Cell: renal tubular epithelial cell lines	Preclinical
	Puerarin109	Animal: DKD animal models	Preclinical
	Liraglutide110	Animal: DKD animal models	Clinically available
	Dapagliflozin111	Human: T2DM patients with kidney disease (CREDENCE and other RCTs); Animal: DKD mouse models	Clinical translation
Promotion of iron export	Puerarin109	Animal: DKD animal models	Preclinical	FPN1/SLC40A1	Upregulation or stabilization of FPN1/SLC40A1 enhances iron efflux and limits iron retention	Decreased renal iron accumulation, reduced tubular epithelial cell damage, attenuated interstitial fibrosis	Improved eGFR, reduced serum creatinine, decreased UACR
	Liraglutide110	Animal: DKD animal models	Clinically available
	Dapagliflozin111,112	Human: T2DM patients with kidney disease (CREDENCE and other RCTs); Animal: DKD mouse models	Clinical translation
Enhancement of iron storage	Paricalcitol11	Animal: DKD mouse models	Preclinical	FTH1/FTL	Increased FTH1/FTL expression promotes ferritin-mediated iron sequestration and reduces the labile iron pool	Reduced lipid peroxidation-induced tubular injury, attenuated glomerulosclerosis, decreased tubular interstitial fibrosis	Reduced proteinuria, improved eGFR, decreased serum BUN and creatinine
	Astragaloside IV90	Animal: STZ-induced and db/db diabetic mice; Cell: renal tubular epithelial cell lines	Preclinical
	Puerarin109	Animal: DKD animal models	Preclinical
	Dapagliflozin111	Human: T2DM patients with kidney disease (CREDENCE and other RCTs); Animal: DKD mouse models	Clinical translation
Modulation of HIF-1α/HMOX1 signaling	Astragaloside IV60	Animal: STZ-induced and db/db diabetic mice; Cell: renal tubular epithelial cell lines	Preclinical	HIF-1α/HMOX1	Regulation of HIF-1α/HMOX1 decreases iron release and oxidative stress under diabetic conditions	Attenuated tubular epithelial cell ferroptosis, reduced renal interstitial inflammation, decreased tubular atrophy	Improved eGFR, reduced proteinuria, decreased serum creatinine
	Ferrostatin-187	Animal: db/db mice	Preclinical
Inhibition of ferritinophagy	Dapagliflozin111	Animal: DKD mouse models	Clinical translation	NCOA4	Suppression of NCOA4-mediated ferritin degradation reduces iron liberation from ferritin stores	Reduced tubular iron overload, attenuated tubular epithelial cell injury, decreased interstitial fibrosis	Improved eGFR, reduced UACR, decreased serum BUN
Direct ferroptosis inhibition/iron lowering	Ferrostatin-187	Animal: db/db mice	Preclinical	ACSL4	Reduction of iron-dependent lipid peroxidation and suppression of ferroptotic signaling	Reduced glomerular sclerosis, attenuated tubular atrophy and interstitial fibrosis, decreased inflammatory cell infiltration	Improved renal histopathology, preserved kidney function, reduced proteinuria
	Rosiglitazone113	Animal: DKD animal models	Clinically available
Multitarget natural or adjunctive approaches	Leech granules80	Animal: DKD mice	Preclinical	TFR1, FPN1, Nrf2, GPX4	Coordinated regulation of iron handling, antioxidant defense, and ferroptosis-related signaling	Reduced renal iron deposition, attenuated tubular epithelial cell injury, decreased glomerular and interstitial fibrosis	Improved eGFR, reduced proteinuria, decreased serum creatinine and BUN
	Quercetin114,115	Animal: STZ-induced diabetic rats, DKD mice	Preclinical	TFR1, FPN1, Nrf2, GPX4
	Notoginsenoside Ft1116	Animal: DKD animal models	Preclinical	TGR5
	Irisin117	Animal: DKD animal models	Preclinical	HMGB1/Nrf2/GPX4
	Magnesium118	Animal: DKD animal models	Preclinical	AMPK/FoxO3a/Nrf2

Notes: Translational stage: Clinical translation indicates that human evidence exists (eg, epidemiological associations, biomarker studies, or post-hoc analyses) but the specific anti-ferroptotic mechanism in DKD requires further RCT validation; Preclinical indicates that evidence is derived exclusively from animal and/or cellular studies; Clinically available indicates that the agent is already approved for clinical use (eg, for T2DM) but its anti-ferroptotic effects in DKD remain to be validated.

Table 2.

Therapeutic Strategies Targeting Antioxidant Defense Systems and Ferroptosis-Suppressive Pathways in Diabetic Kidney Disease

Therapeutic Category	Representative Agents/Strategies	Evidence Source	Translational Stage	Primary Target	Main Mechanism	Associated Outcome
Activation of Nrf2 signaling	Berberine119	Animal: DKD mouse models; Cell: renal tubular epithelial cells	Preclinical	Nrf2	Activation of Nrf2 and downstream antioxidant genes restores redox balance and suppresses lipid peroxidation	Reduction of oxidative stress, ferroptosis, and renal injury
	DDO-1039102	Animal: DKD animal models	Preclinical
	Emodin120	Animal: DKD animal models	Preclinical
	Quercetin114,115	Animal: STZ-induced diabetic rats, DKD mice	Preclinical
	Empagliflozin74,94	Animal: DKD animal models	Clinically available
	Obacunone121	Animal: DKD animal models; Cell: renal tubular epithelial cells	Preclinical
	Fucoidan122	Animal: DKD animal models; Cell: renal tubular epithelial cells	Preclinical
	Fisetin123	Animal: DKD animal models	Preclinical
	Carnosine124	Animal: DKD animal models; Cell: renal tubular epithelial cells	Preclinical
	Naringenin70	Cell: HK-2 cells	Preclinical
Preservation of GPX4 activity	Ginkgolide B125	Animal: DKD animal models	Preclinical	GPX4	Upregulation or stabilization of GPX4 enhances detoxification of lipid peroxides and limits ferroptosis	Protection of podocytes and tubular epithelial cells from diabetic injury
	Vitamin D57	Human: kidney tissue from prediabetic patients; Animal: DKD mouse models; Cell: high glucose-treated renal tubular epithelial cells	Clinical translation
	Paricalcitol11	Animal: DKD mouse models	Preclinical
	Cordycepin99	Animal: DKD animal models	Preclinical
	Vitexin126	Animal: DKD animal models	Preclinical
	Curcumin nanocrystals127	Animal: DKD animal models	Preclinical
Enhancement of system Xc−/SLC7A11	Vitamin D57	Human: kidney tissue from prediabetic patients; Animal: DKD mouse models; Cell: high glucose-treated renal tubular epithelial cells	Clinical translation	SLC7A11	Restoration of cystine uptake and glutathione synthesis strengthens endogenous antiferroptotic capacity	Amelioration of mitochondrial dysfunction, oxidative stress, and cell death
	Paricalcitol11	Animal: DKD mouse models	Preclinical
	Vitexin126	Animal: DKD animal models	Preclinical
	Bone marrow mesenchymal stem cells79	Animal: DKD animal models	Preclinical
	Hirsutine62	Animal: db/db mice	Preclinical
Activation of FSP1/CoQ10 defense	Liraglutide110	Animal: DKD animal models	Clinically available	FSP1/CoQ10	Enhancement of the FSP1–CoQ10–NAD§H pathway suppresses lipid radical propagation independently of GPX4	Reduction of oxidative DNA damage and lipid peroxidation
Modulation of HIF-1α/HO-1-related antioxidant pathways	Astragaloside IV60,90	Animal: STZ-induced and db/db diabetic mice; Cell: renal tubular epithelial cell lines	Preclinical	HIF-1α/HO-1	Rebalancing of HIF-1α/HO-1-associated stress responses reduces ferroptosis-related injury	Improvement of renal oxidative stress and fibrosis
	Shenkang pills128	Animal: DKD animal models	Preclinical
	Ferrostatin-187	Animal: db/db mice	Preclinical
Regulation of stress kinase and inflammatory signaling	Ursolic acid129	Animal: DKD animal models	Preclinical	JAK2/STAT3	Modulation of JAK/STAT, JNK/KEAP1/NRF2, or TGR5 signaling indirectly suppresses ferroptosis	Attenuation of tubular injury, inflammation, and fibrosis
	Human umbilical cord mesenchymal stem cells130	Animal: DKD animal models	Preclinical	JNK/KEAP1/NRF2
	Notoginsenoside Ft1116	Animal: DKD animal models	Preclinical	TGR5
Multitarget natural or adjunctive approaches	Glabridin131	Animal: DKD animal models	Preclinical	VEGF/Akt/ERK	Coordinated inhibition of lipid peroxidation, ROS accumulation, and proferroptotic signaling	Broad protection against ferroptotic kidney injury
	Tanshinone IIA64	Animal: DKD animal models; Cell: podocytes	Preclinical	ELAVL1/ACSL4
	Adaptive antioxidant nanomedicines132	Animal: DKD animal models	Preclinical	GPX4 synthesis
	ALOX5 inhibitors104	Bioinformatics: human data	Tool/method development	ALOX5

Notes: Translational stage: Clinical translation indicates that human evidence exists (eg, epidemiological associations, biomarker studies, or post-hoc analyses) but the specific anti-ferroptotic mechanism in DKD requires further RCT validation; Preclinical indicates that evidence is derived exclusively from animal and/or cellular studies; Clinically available indicates that the agent is already approved for clinical use (eg, for T2DM) but its anti-ferroptotic effects in DKD remain to be validated.

Table 3.

Therapeutic Strategies Targeting Inflammation-Ferroptosis Crosstalk and Translational Opportunities in Diabetic Kidney Disease

Therapeutic Category	Representative Agents/Strategies	Evidence Source	Translational Stage	Primary Target	Main Mechanism	Associated Outcome/Translational Relevance
GLP-1 receptor agonists	Dulaglutide133	Animal: db/db mice	Clinically available	GLP-1R	Suppression of inflammatory signaling and ferroptosis-related markers, together with improvement of iron handling and antioxidant defense	High translational relevance because these agents are already used in type 2 diabetes
Vitamin D/VDR-based interventions	Paricalcitol11	Animal: DKD mouse models	Preclinical	VDR	Enhancement of Klotho/p53 or VDR/Nrf2/HO-1 signaling links anti-inflammatory and antiferroptotic effects	Attractive adjunctive strategies with established clinical use or feasibility
	Vitamin D57	Human: kidney tissue from prediabetic patients; Animal: DKD mouse models; Cell: high glucose-treated renal tubular epithelial cells	Clinical translation
Natural products and traditional medicine	Astragaloside IV60	Animal: STZ-induced and db/db diabetic mice; Cell: renal tubular epithelial cell lines	Preclinical	HIF-1α/HO-1	Simultaneous modulation of oxidative stress, iron metabolism, inflammatory pathways, and ferroptosis suppressors	Provide multitarget therapeutic potential but require stronger translational validation
	Puerarin109	Animal: DKD animal models	Preclinical	TFR1/FPN1
	Schisandrin A97	Animal: DKD animal models	Preclinical	AdipoR1
	Berberine119	Animal: DKD mouse models; Cell: renal tubular epithelial cells	Preclinical	Nrf2/KLF4
	Quercetin115,134	Animal: STZ-induced diabetic rats, DKD mice	Preclinical	Nrf2/HO-1
	Fisetin123,135	Animal: DKD animal models	Preclinical	Nrf2/HO-1/GPX4, ACSL4
	Ursolic acid129	Animal: DKD animal models	Preclinical	JAK2/STAT3
	Glabridin131	Animal: DKD animal models	Preclinical	VEGF/Akt/ERK
	Hederagenin136	Animal: DKD animal models	Preclinical	Smad3/NOX4/SLC7A11
	Rhein137	Animal: DKD animal models	Preclinical	Rac1/NOX1/β-Catenin
Stem cell-based approaches	Bone marrow mesenchymal stem cells79	Animal: DKD animal models	Preclinical	SLC3A2/MAPK	Coordinated suppression of ferroptosis, inflammation, and fibrosis through paracrine and signaling-mediated effects	Promising but currently limited by manufacturing, standardization, and clinical accessibility
	Human umbilical cord mesenchymal stem cells130	Animal: DKD animal models	Preclinical	JNK/KEAP1/NRF2

Notes: Translational stage: Clinical translation indicates that human evidence exists (eg, epidemiological associations, biomarker studies, or post-hoc analyses) but the specific anti-ferroptotic mechanism in DKD requires further RCT validation; Preclinical indicates that evidence is derived exclusively from animal and/or cellular studies; Clinically available indicates that the agent is already approved for clinical use (eg, for T2DM) but its anti-ferroptotic effects in DKD remain to be validated.

Targeting Iron Metabolism

Iron dyshomeostasis is really at the heart of ferroptosis in DKD. So it makes sense that this is a major place to target therapeutically. Think about what happens: too much iron uptake, not enough export, poor sequestration by ferritin, and ferritinophagy releasing even more iron. All of that expands the labile iron pool, which then fuels lipid peroxidation and ferroptotic cell death in kidney cells. Several studies have found that reducing iron entry through TFR1 actually works. There are a number of agents that can do this—vitamin D, astragaloside IV, puerarin, liraglutide, and dapagliflozin, to name a few. They’ve been shown to lower TFR1 expression and ease iron overload in the kidneys.^{57,60,90,109–111} On the flip side, helping iron get out—by restoring FPN1/SLC40A1 function—has also become an important strategy.^109–112 You see this especially with dapagliflozin, liraglutide, and puerarin.

Enhancing iron storage capacity is also protective. Upregulation of ferritin subunits such as FTH1 limits the availability of redox-active iron and suppresses iron-driven lipid damage. This mechanism has been implicated in the renoprotective effects of paricalcitol, astragaloside IV, puerarin, and dapagliflozin.^{11,90,109,111} In addition, regulation of HIF-1α/HMOX1 signaling appears to influence ferroptosis sensitivity under diabetic conditions, although the role of this pathway may be context dependent.^60,87 Inhibiting excessive ferritinophagy, especially through suppression of NCOA4, may further reduce liberation of free iron from ferritin stores. Taken together, these findings support the concept that the correction of intrarenal iron misdistribution is a central therapeutic strategy in DKD.¹¹¹ Representative iron-targeting agents and their major mechanisms are summarized in Table 1.

Targeting the Antioxidant System

A second major therapeutic strategy focuses on restoring endogenous antioxidant defenses that counteract ferroptosis. Because ferroptosis is defined by iron-dependent phospholipid peroxidation, interventions that enhance intracellular antioxidant capacity are particularly attractive in DKD, where persistent hyperglycemia, mitochondrial dysfunction, and metabolic stress amplify oxidative injury. Among currently reported pathways, activation of Nrf2 is the most consistently observed mechanism. A wide range of agents, including berberine, DDO-1039, emodin, quercetin, empagliflozin, obacunone, fucoidan, fisetin, carnosine, and naringenin, have been shown to activate Nrf2 signaling and its downstream antioxidant transcriptional program, thereby reducing reactive oxygen species accumulation and ferroptotic injury.^{70,71,94,102,114,115,119–124,138–140}

Downstream ferroptosis-suppressive systems have also been directly targeted. Preservation or restoration of GPX4 remains one of the most important mechanisms, as GPX4 is essential for detoxifying phospholipid hydroperoxides. Agents such as ginkgolide B, vitamin D, paricalcitol, cordycepin, vitexin, and curcumin nanocrystals have all been reported to maintain GPX4 expression or activity in experimental DKD models.^{11,57,99,125–127} Similarly, enhancement of system Xc⁻/SLC7A11 improves cystine uptake and glutathione synthesis, thereby strengthening cellular resistance to ferroptosis.^62,79 Emerging evidence further suggests that the FSP1/CoQ10 axis, stress kinase pathways such as JAK/STAT and JNK/KEAP1/NRF2, and other redox-regulatory networks may provide additional therapeutic leverage points.^{60,64,87,90,104,110,116,128–132} Overall, these data indicate that impaired antioxidant defense is not merely a downstream consequence of DKD but a tractable and mechanistically relevant therapeutic target. The principal antioxidant and ferroptosis-suppressive strategies are summarized in Table 2.

Regulation of Inflammation

Inflammation and ferroptosis form a bidirectional amplification loop in DKD. Ferroptotic cells release danger-associated molecular patterns and oxidized lipid mediators that can intensify inflammatory signaling, whereas inflammatory stress in turn promotes iron dysregulation, reactive oxygen species accumulation, and lipid peroxidation. This interaction suggests that interventions capable of interrupting inflammation–ferroptosis crosstalk may have particular therapeutic value. Notably, several drug classes already used in diabetes care appear to exert such effects. Dulaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce inflammatory signaling while simultaneously attenuating ferroptosis-related molecular changes.¹³³

A large number of natural compounds and traditional medicines also demonstrate dual anti-inflammatory and antiferroptotic activities. Representative examples include berberine, quercetin, fisetin, astragaloside IV, puerarin, glabridin, rhein, hederagenin, schisandrin A, and ursolic acid. Although their direct clinical translation requires further validation, these agents provide important proof-of-concept that ferroptosis can be modulated through multitarget pharmacological approaches.^{60,97,100,109,115,119,123,129,131,134–137,141,142} In parallel, stem cell-based therapies, such as bone marrow mesenchymal stem cells and human umbilical cord mesenchymal stem cells, appear to suppress ferroptosis while also reducing inflammation and fibrosis, further highlighting the therapeutic relevance of pathway convergence.^79,130 Collectively, these findings indicate that ferroptosis should not be viewed in isolation but rather as part of a broader pathogenic network involving inflammatory and fibrotic signaling. Clinically relevant and translationally promising strategies targeting inflammation–ferroptosis crosstalk are summarized in Table 3.

To facilitate a holistic understanding of the three therapeutic approaches discussed above, we provide a systematic comparison in Table 4. This table summarizes the core logic, primary targets, optimal application stages, advantages, limitations, and translational status of each strategy, allowing readers to quickly assess the relative strengths and weaknesses of iron metabolism targeting, antioxidant system targeting, and inflammation–ferroptosis crosstalk modulation in the context of DKD.

Table 4.

Systematic Comparison of Ferroptosis-Targeted Therapeutic Strategies in Diabetic Kidney Disease

Comparison Dimension	Iron Metabolism Targeting	Antioxidant System Targeting	Inflammation-Ferroptosis Crosstalk Targeting
Core logic	Reduce iron accumulation	Restore antioxidant defenses	Block inflammation-ferroptosis feedback
Primary targets	TFR1, FPN1, FTH1, NCOA4	Nrf2, GPX4, SLC7A11	HMGB1, IL-6, NLRP3
Optimal application	Early prevention	Throughout disease	Inflammation-dominant DKD
Main advantage	Targets upstream events	Eliminates lethal lipid peroxides	Multi-target benefits
Main limitation	Long-term safety unknown	GPX4 specificity limited	May affect immune surveillance
Current evidence	Human + Animal	Animal + Cell	Animal + Cell
Translational stage	Clinical translation / Preclinical	Preclinical	Preclinical

Notes: References for each strategy category are provided in Tables 1–3. Iron metabolism targeting;^{11,57,60,87,90,109–112}Antioxidantsystem targeting;^{11,57,60,62,64,70,71,79,87,90,94,99,102,104,110,114–116,119–132,138–140}Inflammation-ferroptosiscrosstalk targeting.^{60,79,97,100,109,115,119,123,129–131,133–137,141,142}.

Clinical Translation Challenges and Safety Concerns

Despite promising preclinical evidence, several clinical translation challenges remain. First, most ferroptosis inhibitors have been evaluated only in short-term animal studies, with limited data on long-term safety. Chronic iron deprivation may disrupt essential physiological processes, including erythropoiesis, mitochondrial function, and immune homeostasis. Second, GPX4 is essential for normal cell survival, and its systemic inhibition could lead to off-target toxicity in non-renal tissues. The development of kidney-specific delivery systems is therefore critical to minimize systemic side effects while maximizing local therapeutic efficacy. Third, the optimal timing of ferroptosis-targeted intervention—whether early in the disease course or at advanced stages—remains undefined. Given that ferroptosis contributes to both early tubular injury and progressive fibrosis, earlier intervention may yield greater benefit, but this hypothesis requires prospective testing. Fourth, patient selection biomarkers are lacking; without reliable tools to identify individuals most likely to respond to ferroptosis-targeted therapies, clinical trial design and patient stratification will remain challenging. Fifth, the relationship between ferroptosis inhibition and existing DKD therapies requires further exploration. While SGLT2 inhibitors and RAAS blockers remain the standard of care, whether ferroptosis inhibitors can provide additive benefit in patients already receiving optimal therapy has not been established. Future research should prioritize well-designed randomized controlled trials that incorporate biomarker-driven patient selection, long-term safety monitoring, and head-to-head or add-on comparisons with current DKD therapies to determine whether ferroptosis-targeted strategies can meaningfully improve clinical outcomes.

Conclusion

This review consolidates current evidence linking iron dysregulation and ferroptosis to the pathogenesis of diabetic kidney disease. We have systematically identified three interconnected drivers—iron metabolism disturbance, lipid peroxidation, and antioxidant defense failure—that collectively drive ferroptotic renal cell death. Importantly, this review clarifies that ferroptotic damage is cell-type specific, with podocytes, tubular epithelial cells, mesangial cells, and glomerular endothelial cells exhibiting distinct vulnerabilities and regulatory networks. Furthermore, we have delineated how ferroptosis engages in bidirectional crosstalk with oxidative stress and inflammation, forming self-amplifying loops that promote tubular injury, interstitial fibrosis, and progressive renal dysfunction. By collating evidence from human, animal, and cellular studies separately, this review provides a framework for distinguishing clinically validated observations from preclinical findings, thereby facilitating assessment of translational relevance.

From a therapeutic perspective, strategies targeting iron metabolism, antioxidant defenses, and inflammation-ferroptosis crosstalk have demonstrated efficacy in preclinical models. However, none of these strategies have been validated in large-scale randomized controlled trials for DKD patients. Critical gaps persist: optimal patient selection criteria remain undefined; long-term safety profiles, particularly regarding chronic iron deprivation and potential off-target effects of GPX4 inhibition, have not been established; and interactions with existing DKD therapies—including RAAS blockers and SGLT2 inhibitors—require systematic evaluation. The lack of validated, kidney-specific biomarkers further impedes clinical trial design and personalized treatment.

In conclusion, ferroptosis is a biologically and mechanistically compelling pathway in DKD progression, and the evidence synthesized in this review establishes a foundation for future translational research. However, therapeutic translation remains at an early experimental stage. Cautious interpretation of preclinical findings is warranted. Achieving clinical application will require rigorous biomarker validation, kidney-targeted delivery systems, and well-designed clinical trials with long-term safety monitoring. Until these milestones are reached, ferroptosis-targeted therapies should be viewed as a promising experimental strategy rather than a clinically ready option for DKD management.

Funding Statement

The research was supported by Chongqing Science and Health Joint Medical Research General Project (2026MSXM024), Postgraduate Research and Innovation Project of Chongqing Municipality (CYS25369), Science and Health Joint Project of Dazu District Science and Technology Bureau (DZKJ2024JSYJ-KWXM1002, DZKJ2025JSYJ-KWXM1036), Research project of the State Administration of Traditional Chinese Medicine on collaborative chronic disease management of traditional Chinese medicine and western medicine (CXZH2024087), Chongqing Medical Leading Talent Project (YXLJ202514), Chronic Disease Management Research Project of National Health Commission Capacity Building and Continuing Education Center (GWJJMB202510024191), and General project of Chongqing Natural Science Foundation (CSTB2023NSCQ-MSX0246).

Abbreviations

DKD, diabetic kidney disease; ESRD, end-stage renal disease; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; TFR1, transferrin receptor 1; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GPX4, glutathione peroxidase 4; system Xc−, cystine/glutamate antiporter system Xc−; DMT1, divalent metal transporter 1; ZIP, ZRT/IRT-like protein; STEAP3, six-transmembrane epithelial antigen of prostate 3; LTCC, L-type calcium channel; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; NCOA4, nuclear receptor coactivator 4; FPN1, ferroportin 1; ACSL4, acyl-CoA synthetase long-chain family member 4; ALOX15, arachidonate 15-lipoxygenase; FSP1, ferroptosis suppressor protein 1; CoQ10, coenzyme Q10; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; BOLD-MRI, blood oxygen level-dependent magnetic resonance imaging; ZIP14, Zrt- and Irt-like protein 14; HMOX1, heme oxygenase 1; PHGDH, phosphoglycerate dehydrogenase; YB1, Y-box binding protein 1; Akt, protein kinase B; Nrf2, nuclear factor erythroid 2-related factor 2;, dipeptidase 1; EZH2, enhancer of zeste homolog 2; IREB2, iron-responsive element binding protein 2; HIF-1α, hypoxia-inducible factor 1-alpha; VDR, vitamin D receptor; SGLT2, sodium-glucose cotransporter 2; ZNF281, zinc finger protein 281; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; HMGB1, high mobility group box 1; PTGS2, prostaglandin-endoperoxide synthase 2; NLRP3, NLR family pyrin domain containing 3; PI3K, phosphoinositide 3-kinase; TLR4, toll-like receptor 4; NF-κB, nuclear factor kappa-B; TNF-α, tumor necrosis factor-alpha; HO-1, heme oxygenase-1; NQO1, NAD(P)H quinone dehydrogenase 1; ALOX5, arachidonate 5-lipoxygenase; JNK, c-Jun N-terminal kinase; KEAP1, Kelch-like ECH-associated protein 1; GLP-1, glucagon-like peptide-1; METTL3, methyltransferase-like 3; YTHDF3, YTH N6-methyladenosine RNA binding protein 3; m6A, N6-methyladenosine.

Data Sharing Statement

Data sharing is not applicable to this article as no new data were created or analysed in this study. The material supporting the findings of this review is available from the cited sources.

Author Contributions

MengLing Zhang: Writing – original draft, Formal Analysis, Data Curation,Writing – review & editing, Visualization, Funding acquisition. HongLiang Lv: Resources, Data Curation, Visualization, Writing – review & editing, Supervision. Shuang Fan: Conceptualization, Methodology, Writing – review & editing, Supervision. QiNan Wu: Conceptualization, Formal analysis, Methodology, Writing – review & editing, Supervision, Funding acquisition. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.